Glioblastoma multiforme (GBM) is the most common primary brain tumor and is associated with a median survival of 9-12 months, despite years of research and a growing body of data. Global DNA hypomethylation is frequent in primary GBM and preliminary data indicates that it is associated with increased tumor aggressiveness and decreased patient survival. The central hypothesis of the proposal is that DNA hypomethylation evolves over time, increasing aggressiveness through concurrent oncogene activation, loss of imprinting, and genome instability caused by repetitive element hypomethylation. First, DNA methylation patterns on the genome-wide scale will be deciphered by the development, optimization and validation of a new method, MeDIP-seq. This methodology will elucidate where and when DNA hypomethylation occurs using paired patient primary and recurrent tumor samples and a mouse orthotopic model of patient primary tumors. In addition, thoproving the understanding of genetic and environmental factors related to GBM and 2) characterizing GBM at the molecular level (both of which are Research Priorities identified by the Brain Tumor Progress Review Group). The proposal also addresses NIH Roadmap's "epigenomics of human health and disease" by examining fundamental epigenomic changes and mechanisms underlying GBM. Overall, the proposed experiments are expected to discover new pathways controlling GBM aggressiveness and identify potential targets for molecular-based therapeutics, leading to better treatments for GBM. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM) is most common primary brain tumor and the prognosis for most patients is dire, with a median survival of 9-12 months. Current treatment strategies are clearly insufficient and innovative approaches are required to improve survival for GBM patients. This proposal will examine the relationship between a previously under-studied yet common alteration to GBM DNA, known as hypomethylation, and tumor aggressiveness using patient samples and a mouse model, with the ultimate goal of finding new targets for rationally designed drugs. 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